Sprouty2-a Novel Therapeutic Target in the Nervous System?

Clinical trials applying growth factors to alleviate symptoms of patients with neurological disorders have largely been unsuccessful in the past. As an alternative approach, growth factor receptors or components of their signal transduction machinery may be targeted directly. In recent years, the search for intracellular signaling integrator downstream of receptor tyrosine kinases provided valuable novel substrates. Among them are the Sprouty proteins which mainly act as inhibitors of growth factor-dependent neuronal and glial signaling pathways. In this review, we summarize the role of Sprouties in the lesioned central and peripheral nervous system with particular reference to Sprouty2 that is upregulated in various experimental models of neuronal degeneration and regeneration. Increased synthesis under pathological conditions makes Sprouty2 an attractive pharmacological target to enhance intracellular signaling activities, notably the ERK pathway, in affected neurons or activated astrocytes. Interestingly, high Sprouty2 levels are also found in malignant glioma cells. We recently demonstrated that abrogating Sprouty2 function strongly inhibits intracranial tumor growth and leads to significantly prolonged survival of glioblastoma bearing mice by induction of ERK-dependent DNA replication stress. On the contrary, knockdown of Sprouty proteins increases proliferation of activated astrocytes and, consequently, reduces secondary brain damage in neuronal lesion models such as kainic acid-induced epilepsy or endothelin-induced ischemia. Furthermore, downregulation of Sprouty2 improves nerve regeneration in the lesioned peripheral nervous system. Taken together, targeting Sprouties as intracellular inhibitors of the ERK pathway holds great promise for the treatment of various neurological disorders including gliomas. Since the protein lacks enzymatic activities, it will be difficult to develop chemical compounds capable to directly and specifically modulate Sprouty functions. However, interfering with Sprouty expression by gene therapy or siRNA treatment provides a realistic approach to evaluate the therapeutic potential of indirectly stimulating ERK activities in neurological disease.